The risk of developing insulin dependent diabetes mellitus (IDDM) is intimately associated with an individual's immune system as expressed through the class II HLA genes. It is clear however, that inheritance of HLA genes which confer the highest risk of developing IDDM does not mean that an individual will develop the disease. In addition to environmental factors, several lines of evidence suggest that additional, non-HLA, genetic factor(s) may be necessary to acquire IDDM. We have initiated a search for additional genetic factors by systematically searching for linkage between genetic loci and IDDM families having 2 or more affected children. Results to date suggest that we have identified one, and possibly two, locations for IDDM susceptibility genes. Evaluations of these linkages will be the focus of our continued research. This will consist of collecting and testing additional IDDM families to verify the linkage using a variety of genetic approaches. If the evidence for linkage holds, we will evaluate several candidate genes in the region and, if necessary, carry out an intensive molecular genetic analysis to identify the susceptibility gene. This will consist primarily of saturating the region with highly polymorphic genetic markers which should map the susceptibility locus to a small part of the chromosome: a necessary prelude to identify the gene involved by positional cloning techniques. In addition, we will continue to search for other non-HLA loci on other chromosomes which might lead to IDDM susceptibility. This search will be carried out using our collection of over 350 DNA markers which reveal polymorphic loci. This study will continue the collaboration with Dr. Michael Sheehy (AgriCetus Corp., Madison, WI) and Dr. Glenys Thomson (Dept. of Genetics, University of California, Berkeley). Identification and characterization of nonHLA loci associated with IDDM susceptibility would be a significant step toward providing pre-symptomatic diagnosis and risk assessment.